Growing evidence suggests that patients with diverse forms of solid tumors (breast, colon, lung, ovarian, renal and head-and-neck carcinoma, melanoma, among others) that contain non-encapsulated, organized clusters of immune cell infiltrates (i.e. termed tertiary lymphoid structures (TLS) or ectopic lymphoid organs (ELO)) have significantly better clinical prognoses (superior overall survival, progression-free survival and/o responsiveness to chemotherapy) than comparable patients that lack such infiltrates. Notably, tumor-associated TLS have been suggested to serve as important sites of extranodal T cell priming, and to be characterized by mature (DC-LAMPhi+) DC deposits in intimate contact with recruited T cell populations around MECA-79+ (aka peripheral node addressin; PNAd, a marker of high endothelial venules/HEV in lymph nodes) blood vessels within the tumor microenvironment (TME). Similar results have been reported in murine solid cancer models in both wild-type and peripheral lymph node-deficient recipient animals. Nave lymphocytes have been identified in TLS within pulmonary lesions of patients with lung cancer, making it likely that these immune cells encounter their cognate antigen for the first time and develop into antigen-specific T effector cells within the TME (rather than in peripheral lymph nodes) in vivo. TLS featuring DC/Type-1 T cell clusters proximal to B cell nests have also been identified in human non-small-cell lung cancer (NSCLC) specimens, in association with improved long-term survival. B cells in NSCLC-associated TLS also appear to undergo all stages of their normal differentiation programming from nave precursors, including somatic hypermutation and Ig class-switching, development of plasma cells and production of (anti-tumor) antibodies. These data suggest the hypothesis that at under the appropriate conditions, tumors may be converted into functional lymphoid organs in which protective immunity may be effectively primed. Our proposal will employ informative wild-type, mutant and transgenic mouse models to determine the cellular and molecular mechanisms underlying Tbet- and IL-36/IL-36R-mediated therapeutic TLS development and induction of protective anti-tumor T cells capable of policing disseminated disease, and evaluate how the therapeutic benefits associated with the conversion of tumor sites into lymphoid organs can be further enhanced by cancer vaccines, adoptive cell therapies (ACT) and immune checkpoint blockade (ICB).